The Perils of Losing Focus

T cells are single-minded pathogen-fighting machines. They take specialization to the next level—to ensure they only attack infected cells with the correct target, they actually rearrange their DNA so that the T cell receptors (TCRs) on an individual T cell can only respond to one peptide/major histocompatibility complex combination. But even T cells slip up sometimes: A small subset of T cells in people actually expresses two TCRs. Now, Morris et al. demonstrate that these dual TCR T cells contribute disproportionately to acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT).

The authors examined dual TCR T cells from patients with aGVHD—where the transplanted immune cells attack their new host—and found that they had an activated phenotype and, when stimulated, produced cytokines pathogenic in aGVHD. These cells could respond to mismatched recipient human leukocyte antigen (HLA), such as would be found with allogeneic transplants, recognizing both major and minor histocompatibility antigens. What’s more, they contributed disproportionately to the repertoire of T cells that could recognize mismatched HLA. Although it remains to be determined why exactly these dual TCR T cells are more likely to attack a different “self,” selective depletion of these cells from the donor graft may provide a new avenue for combating aGVHD.